The latest medical research on Immunology & Allergy
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HIV viral suppression in children and adolescents two years after transition to dolutegravir: a multicentre cohort study.AIDS
Treatment failure is common among children and adolescents with HIV. Antiretroviral therapy (ART) containing dolutegravir has recently been rolled out across Africa, though long-term real-world data in paediatric populations are lacking. Here, we report treatment outcomes among children and adolescents in Lesotho who transitioned from non-nucleoside reverse transcriptase inhibitor- (NNRTI-) to dolutegravir-based ART through two years' follow-up.
Data were derived from two open cohort studies in Lesotho. Children and adolescents aged < 18 years who transitioned from NNRTI- to dolutegravir-based ART at least 18 months before data closure were included. We report viral load results <12 months before, 12 (window: 6-17) months after, and 24 (window: 18-29) months after transition to dolutegravir. Associations of pre-transition demographic and clinical factors with 24-month viraemia were assessed through multivariable logistic regression.
Among 2126 included individuals, 1100 (51.7%) were female, median age at transition to dolutegravir was 14.0 years (interquartile range [IQR] 11.5-15.8), and median time taking ART at transition was 7.6 years (IQR 4.4-10.6). Among those with a viral load result at the respective time points, viral suppression to <50 copies/mL was achieved by 1635/1973 (82.9%) <12 months before, 1846/2012 (91.8%) 12 months after, and 1725/1904 (90.6%) 24 months after transition to dolutegravir. Pre-transition viraemia was associated with viraemia at 24 months, though >80% of individuals with pre-transition viraemia achieved resuppression to <50 copies/mL at 24 months.
The proportion of children and adolescents with viral suppression increased after transition to dolutegravir, though further progress is needed to reach global targets.
Inhibitory Effect of Apolipoprotein A-I on Eosinophils in Allergic Rhinitis in vitro and in vivo.Journal of Asthma and Allergy
Eosinophils have pivotal roles in the development of allergic rhinitis (AR) through the release of cytotoxic substances. Apolipoprotein A-I (Apo-AI) exhibits a strong inhibitory effect on eosinophil infiltration in allergic diseases. Nevertheless, the precise impact of Apolipoprotein A-I on eosinophils remains uncertain.
Our study recruited a total of 15 AR children and 15 controls. The correlation between Apo-AI expression and the counts of blood eosinophils was examined. Flow cytometry was employed to assess the role of Apo-AI in eosinophil apoptosis and adhesion. The Transwell system was performed to conduct the migration assay. An animal model using AR mice was established to test the effect of Apo-AI on eosinophils.
Serum Apo-AI were negatively related to eosinophils counts and eosinophil chemotactic protein levels in AR. Apo-AI exerts a pro-apoptotic effect while also impeding the processes of adhesion, migration, and activation of eosinophils. The apoptosis triggered by Apo-AI was facilitated through the phosphoinositide 3-kinase (PI3K) pathway. The chemotaxis and activation of eosinophils, which are influenced by Apolipoprotein A-I, are regulated through the PI3K and MAPK signaling pathways. Apo-AI treated mice presented with decreased blood and nasal eosinophilic inflammation as well as down-regulated eosinophil related cytokines.
Our findings provide confirmation that Apo-AI exhibits inhibitory effects on the function of eosinophils in allergic rhinitis. This suggests that Apo-AI holds potential as a therapeutic target for future treatment strategies.
HIV-1 drug resistance and genetic diversity in people with HIV-1 in Cape Verde, 2019-2021.AIDS
To characterize the genetic diversity and drug resistance profiles of people with HIV-1 failing ART in Cape Verde (CV).
The HIV-1 pol gene was sequenced in individuals with a detectable viral load (VL). HIV-1 genetic diversity was determined by phylogenetic analysis. Drug resistance mutation patterns and resistance phenotypes were estimated using the Stanford algorithm.
VL was detected in 73 of 252 (29%) enrolled participants and sequencing data were produced for 58 (79%) participants. CRF02_AG strains predominated (46.5%), followed by subtype G (22.4%). Most patients (80%) had mutations conferring resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) (67%), nucleoside reverse transcriptase inhibitors (55%), integrase inhibitors (10%) and/or protease inhibitors (7%) used in CV, a significant increase compared to a study conducted in 2010-2011. The most common mutations were M184 V/I (43%), K103N/S (36%) and G190A/S (19%). NNRTI resistance was associated with younger age and exposure to two or more drug regimens.
The HIV-1 epidemic in Cape Verde is mainly driven by CRF02_AG and subtype G. Resistance to NNRTIs and/or NRTIs is highly prevalent and resistance to LPV/r and DTG is emerging. Our results support the use of DTG-based first-line ART and PI-based regimens for patients with virological failure, but emerging resistance to LPV/r and DTG is a concern. Continued monitoring of drug resistance is essential to ensure adequate health care for PLWH in Cape Verde.
Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy: 96-week pooled analysis.AIDS
To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy.
A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/mL) and changes in CD4+ cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test.
At OLE Week 96, participants who switched to B/F/TAF (N=519) maintained high levels of virologic suppression (99.5% and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4+ cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events (AEs) after switching, with diarrhea, weight gain and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 AEs or serious AEs. Two participants discontinued B/F/TAF due to treatment-related AEs. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups.
This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.
Differences in internalized HIV stigma across subpopulations of people living with HIV in care across the US.AIDS
Few studies have examined which subgroups of people with HIV (PWH) carry the greatest burden of internalized HIV stigma (IHS), which may be important to care provision and interventions.
PWH in the CFAR Network of Integrated Clinical Systems (CNICS) longitudinal, US-based, multisite, clinical care cohort completed tablet-based assessments during clinic visits including a 4-item, Likert scale (low 1-5 high), IHS instrument. Associations between sociodemographic characteristics and IHS scores were assessed in adjusted linear regression models.
12,656 PWH completed the IHS assessment at least once from February 2016 to November 2022, providing 28,559 IHS assessments. At baseline IHS assessment, the mean age was 49 years, 41% reported White, 38% Black/African American, and 16% Latine race/ethnicity, and 80% were cisgender men. The mean IHS score was 2.04, with all subgroups represented among those endorsing IHS. In regression analyses, younger PWH and those in care fewer years had higher IHS scores. In addition, cisgender women vs. cisgender men, PWH residing in the West vs. the Southeast, and those with sexual identities other than gay/lesbian had higher IHS scores. Compared with White-identifying PWH, those who identified with Black/African American or Latine race/ethnicity had lower IHS scores. Age stratification revealed patterns related to age category, including specific age-related differences by gender, geographic region and race/ethnicity.
IHS is prevalent among PWH, with differential burden by subgroups of PWH. These findings highlight the benefits of routine screening for IHS and suggest the need for targeting/tailoring interventions to reduce IHS among PWH.
Impact of Lung Function on Asthma Exacerbation Rates in Children Treated with Dupilumab: The VOYAGE Study.Journal of Asthma and Allergy
Severe, uncontrolled asthma and asthma exacerbations in children are associated with abnormal lung function and airway development, and increased risk of chronic obstructive lung disease in adulthood. The rationale for this post hoc analysis was to explore the relationship between changes in asthma exacerbation rates and lung function in children treated with dupilumab.
This post hoc analysis included children aged 6 to 11 years with uncontrolled, moderate-to-severe type 2 asthma (blood eosinophils ≥150 cells/μL or fractional exhaled nitric oxide ≥20 ppb) who received dupilumab or placebo in the phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959). Endpoints were the proportion of patients achieving clinically meaningful improvements (≥5% or ≥10%) in pre-bronchodilator percent-predicted forced expiratory volume in 1 second (ppFEV1) by Week 12, annualized severe asthma exacerbation rates from Week 12-52, and mean change from baseline in ppFEV1 to Week 12.
At Week 12 of VOYAGE, 141/236 (60%) of children treated with dupilumab and 57/114 (50%) of children receiving placebo showed improvements of ≥5% in ppFEV1; 106/236 (45%) children receiving dupilumab and 36/114 (32%) receiving placebo achieved improvements in ppFEV1 ≥10%. During the Week 12-52 treatment period, dupilumab vs placebo significantly reduced severe exacerbation rates in all subgroups by 52-60% (all P<0.05). Dupilumab treatment resulted in rapid and sustained improvements in ppFEV1 (Week 12 least squares mean difference [95% CI] vs placebo: 3.54 [0.30, 6.78] percentage points; P=0.03) in children who achieved improvements of ≥5%.
Dupilumab vs placebo significantly improved pre-bronchodilator ppFEV1, with a higher proportion of patients achieving a clinically meaningful response at Week 12. Dupilumab also significantly reduced severe exacerbation rates, independent of pre-bronchodilator ppFEV1 response at Week 12.
Activation of Notch1-GATA3 pathway in asthma bronchial epithelial cells induced by acute PM2.5 exposure and the potential protective role of microRNA-139-5p.J Asthma
PM2.5 is closed linked to asthma exacerbation. The Notch1 pathway acts as an important pathway, ultimately inducing T-helper cells that express GATA3 and its corresponding Th2 cytokines. The regulatory effects of miR-139-5p on the Notch1 pathway have been indicated in cancer. However, studies on miR-139-5p have not applied asthma related models. The role of miR-139-5p and its regulatory effects on the Notch1-GATA3 pathway in asthma exacerbation induced by acute PM2.5 exposure has not been elucidated. We hypothesize that acute PM2.5 exposure induces asthma exacerbation by regulating the expression of miR-139-5p and activating the Notch1-GATA3 pathway.
We first employed Diseased Human Bronchial Epithelial Cells-Asthma cells to establish an in vitro model of acute exposure to PM2.5, and explored the relationship between the different concentrations and durations of acute PM2.5 exposure and the activation of Notch1-GATA3 pathway. We investigated the protein and mRNA expression changes of Notch1, upstream Jagged1, downstream GATA3, as well as the regulatory effect of miR-139-5p involved in it.
The miR-139-5p expression increased within 24 hours of PM2.5 exposure. However, if PM2.5 exposure was sustained, miR-139-5p expression turned to decrease, accompanied by upregulations of the mRNA and protein expression of Notch1-GATA3 pathway. Overexpression of miR-139-5p blocked Notch1-GATA3 pathway activation induced by acute PM2.5 exposure.
Acute PM2.5 exposure can activate Notch1-GATA3 pathway in asthma bronchial epithelial cells model, which might be involved in PM2.5-induced asthma exacerbation. miR-139-5p has a potential protective role of inhibiting PM2.5-induced asthma airway inflammation by targeting Notch1.
Examining Incidence of Diabetes in People Living with HIV: Tracking the Shift in Traditional and HIV-related Risk Factors.AIDS
The risk factors of diabetes mellitus (DM) in people with HIV (PWH) may be dynamic in a life course manner. This study aimed to describe incidence of DM and investigate the trajectory of changes in risk factor associated with DM incidence over around 15 years among a statewide cohort of PWH in South Carolina (SC).
Data were retrieved from the integrated statewide electronic health records between 2006 and 2020 in SC. Separate subgroup analysis was conducted according to the patients' different follow up duration (i.e., 5, 10, and 15 years) to observe the evolving risk factors of DM development, using multivariable logistic regressions.
The DM incidence among a total of 9115 PWH was 8.9 per 1000 person-years. In the overall model, being >60 years old, hypertension, and obesity were positively associated with DM while alcohol consumption, years of HIV diagnosis and high percentage days of viral suppression were negatively associated with the outcome. In the subgroup analyses, similar risk factors were observed. The odds of DM increased in a graded fashion with age. Hypertension was positively associated with DM in all groups and retention to care was negatively associated with the outcome in groups 1 and 3.
This large-scale population-based study has revealed a relatively lower incidence of DM among PWH than some other US States. The evolving risk factors over time underline the need for maintaining retention to care to prevent the occurrence of DM.
Age-associated dementia among older people aging with HIV in the US: a modeling study.AIDS
Almost 400 000 people with HIV (PWH) in the United States are over age 55 years and at risk for age-associated dementias (AAD), including Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID). We projected the cumulative incidence and mortality associated with AAD among PWH at least 60 years in the United States compared with the general population.
Integrating the CEPAC and AgeD-Pol models, we simulated two cohorts of male and female individuals at least 60 years old: PWH, and general US population. We estimated AAD incidence and AAD-associated mortality rates. Projected outcomes included AAD cumulative incidence, life expectancy, and quality-adjusted life-years (QALYs). We performed sensitivity and scenario analyses on AAD-specific (e.g. incidence) and HIV-specific (e.g. disengagement from HIV care) parameters, as well as premature aging among PWH.
We projected that 22.1%/16.3% of 60-year-old male individuals/female individuals with HIV would develop AAD by 80 years compared with 15.9%/13.3% of male individuals/female individuals in the general population. Accounting for age-associated and dementia-associated quality of life, 60-year-old PWH would have a lower life expectancy (QALYs): 17.4 years (14.1 QALYs) and 16.8 years (13.4 QALYs) for male and female individuals, respectively, compared with the general population [men, 21.7 years (18.4 QALYs); women, 24.7 years (20.2 QALYs)]. AAD cumulative incidence was most sensitive to non-HIV-related mortality, engagement in HIV care, and AAD incidence rates.
Projected estimates of AAD-associated morbidity, mortality, and quality of life can inform decision-makers and health systems planning as the population of PWH ages. Improved AAD prevention, treatment, and supportive care planning are critical for people aging with HIV.
Relationships between plasma neurofilament light chain protein, cognition, and brain aging in people with HIV.AIDS
Neurofilament light chain protein (NfL) is a marker of neuronal injury and neurodegeneration. Typically assessed in cerebrospinal fluid, recent advances have allowed this biomarker to be more easily measured in plasma. This study assesses plasma NfL in people with HIV (PWH) compared to people without HIV (PWoH), and its relationship with cognitive impairment, cardiovascular risk, and a neuroimaging metric of brain aging (brain-age gap).
Plasma NfL was compared between PWoH and PWH and assessed for relationships with age, HIV clinical markers, cardiovascular disease risk, cognition, and brain-age gap (difference between a brain-predicted age and chronological age).
Plasma NfL was not significantly different between PWoH and PWH. Higher NfL related to increasing age in both groups. Plasma NfL was not associated with typical HIV disease variables. Within PWH, NfL was higher with higher cardiovascular risk, cognitive impairment and a greater brain-age gap.
Virally suppressed PWH who are cognitively normal likely do not have significant ongoing neurodegeneration, as evidenced by similar plasma NfL compared to PWoH. However, NfL may represent a biomarker of cognitive impairment and brain aging in PWH. Further research examining NfL with longitudinal cognitive decline is needed to understand this relationship more fully.
Higher CCR5 density on CD4+ T cells in mothers and infants is associated with increased risk of in-utero HIV-1 transmission.AIDS
CCR5-tropic viruses are preferentially transmitted during perinatal HIV-1 infection. CCR5 density on CD4+ T cells likely impacts susceptibility to HIV-1 infection.
CCR5 density, together with frequencies of CD4+ and CD8+ T cells expressing immune activation (CCR5, ICOS and HLA-DR) and immune checkpoint (TIGIT and PD-1) markers, were measured in whole blood from the dyads close to delivery.
Compared with mothers who did not transmit, mothers who transmitted HIV-1 had less exposure to ART during pregnancy (P = 0.015) and higher plasma viral load close to delivery (P = 0.0005). These mothers, additionally, had higher CCR5 density on CD4+ and CD8+ T cells and higher frequencies of CCR5, ICOS and TIGIT-expressing CD8+ T cells. Similarly, compared with infants without HIV-1, infants with HIV-1 had higher CCR5 density on CD4+ and CD8+ T cells and higher frequencies of CCR5, TIGIT, and PD-1-expressing CD4+ and CD8+ T cells as well as higher frequencies of HLA-DR-expressing CD8+ T cells. CCR5 density on maternal CD4+ T cells remained significantly associated with transmission after adjusting for maternal viral load and CD4+ T cell counts. Mother-infant dyads with shared high CCR5 density phenotypes had the highest risk of transmission/acquisition of infection compared with dyads with shared low-CCR5 density phenotypes.
This study provides strong evidence of a protective role for a combined mother-infant low CD4+ T-cell CCR5 density phenotype in in-utero transmission/acquisition of HIV-1.
Emergency Management and Asthma Risk in Young Medicaid-Enrolled Children with Recurrent Wheeze.J Asthma
To describe clinical characteristics of young children presenting to the emergency department (ED) for early recurrent wheeze, and determine factors associated with subsequent persistent wheeze and risk for early childhood asthma.
Retrospective cohort study of Medicaid-enrolled children 0-3 years old with an index ED visit for wheeze (e.g., bronchiolitis, reactive airway disease) from 2009-13, and at least one prior documented episode of wheeze at an ED or primary care visit. The primary outcome was persistent wheeze between 4-6 years of age. Demographics and clinical characteristics were collected from the index ED visit. Logistic regression was used to estimate the association between potential risk factors and subsequent persistent wheeze.
During the study period, 41,710 children presented to the ED for recurrent wheeze. Mean age was 1.3 years; 59% were male, 42% Black, and 6% Hispanic. At index ED visits, the most common diagnosis was acute bronchiolitis (40%); 77% of children received an oral corticosteroid prescription. Between 4-6 years of age, 11,708 (28%) children had persistent wheeze. A greater number of wheezing episodes was associated with an increased odds of ED treatment with asthma medications. Subsequent persistent wheeze was associated with male sex, Black race, atopy, prescription for bronchodilators or corticosteroids, and greater number of visits for wheeze.
Young children with persistent wheeze are at risk for childhood asthma. Thus, identification of risk factors associated with persistent wheeze in young children with recurrent wheeze might aid in early detection of asthma and initiation of preventative therapies.